Mutationsinthecardiacryanodinereceptor(RYR2)havebeenassociatedwithcardiacarrhythmias.Specifically,catecholaminergicpolymorphicventriculartachycardia(CPVT)isaninheritedautosomaldominantdiseasethatistypicallymanifestedduringchildhoodasanexercise-inducedtachycardiathatcanprogresstoarrhythmiasduringexercise(orstress)andresultinsuddendeath.Approximately40%ofpatientswithCPVTexhibitadefectinRYR2thathasbeenassociatedwithincreasedreleaseofCa++ fromtheSR.ThemutationinRYR2mayinvolvesubstitutionofahighlyconservedaminoacid,whichdiffersfrommalignanthyperthermia,inwhichsplicingerrorsordeletionswithinRYRhavebeenreported.Itishypothesizedthatduringperiodsofexerciseorstress,increasedlevelsofintracellularCa++ (becauseofthecombinedeffectsofβ-adrenergicstimulationandincreasedactivityofthemutatedRYR2)promotethedevelopmentofdelayedafterdepolarizationsandhencearrhythmias.Elevationofintracellular[Ca++]duringdiastoleisthoughttopromotethedevelopmentofdelayedafterdepolarizationsthroughactivationofthe3Na+-Ca++ antiporter,whereinCa++ extrusionduringdiastoleresultsinanetinwardcurrentsufficienttodepolarizethecelltothethresholdforanactionpotential.TreatmentofCPVTinvolvesantiadrenergictherapy(withβ-adrenergicantagonists)or(forunresponsivepatients)animplanteddefibrillator.
Stretching of the heart increases the force of contraction both in vivo and in vitro and is an intrinsic mechanism for regulating contractile force. In contrast, skeletal muscle typically exhibits maximal tension at resting length. Stretching of the heart in vivo occurs during times of increased venous return of blood to the heart (e.g., during exercise or when the heart rate is slowed, or both). The Frank-Starling law of the heart refers to this ability of the heart to increase its force of contraction when stretched, which occurs at •Fig. 13.4 Sympatheticstimulationoftheheartresultsinanincreaseincytosoliccyclicadenosinemonophosphate(cAMP)andhencephosphorylationofseveralproteinsbyproteinkinaseA(PKA).AnAkinaseanchorprotein(AKAP)adjacenttotheL-typecalciumchannelfacilitatesphosphorylationofthischannelandpossiblynearbysarcoplasmicreticulumcalciumchannels.OtherproteinsphosphorylatedbyPKAincludephospholamban(PLN)andtroponinI.Muscarinicagonists(e.g.,acetylcholine[ACh]),ontheotherhand,inhibitthissympatheticcascadebyinhibitingtheproductionofcAMPbyadenylatecyclase(AC).β-AR,β-adrenergicreceptor;ATP,adenosinetriphosphate;Gi,inhibitoryGprotein;M2Rec,muscarinicacetylcholineM2receptor;Reg,regeneratinggenereceptor.(RedrawnfromBersDM.Cardiacexcitation-contractioncoupling.Nature 2002;415:198.) times of increased venous return (Fig. 13.6A
The importance of this mechanism is that it helps the heart pump whatever volume of blood it receives. Thus when the heart receives a lot of blood, the ventricles are stretched, and the force of contraction is increased, which ensures ejection of this extra volume of blood. Stretching of cardiac muscle also increases passive tension, which helps prevent overstretching of the heart. This passive resistance in the heart is greater than that in skeletal muscle and is attributed to both extracellular matrix (connective tissue) and intracellular elastic proteins (titin).